Non-flushing niacin analogues, and methods of use thereof

ABSTRACT

One aspect of the present invention relates to substituted pyridines and pharmaceutically acceptable salts thereof that are active against a range of mammalian maladies. Another aspect of the invention relates to a pharmaceutical composition, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. The present invention also relates to methods of treating a range of mammalian maladies or conditions, including but not limited to hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary artery disease, congestive heart failure, cardiovascular disease, hypertension, coronary heart disease, angina, pellagra, Hartnup&#39;s syndrome, carcinoid syndrome, arterial occlusive disease, obesity, hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes, Alzheimer&#39;s disease, lipodystrophy, or dyslipidemia, raising serum high-density lipoprotein (HDL) levels, and lowering serum low-density lipoprotein (LDL) levels.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/514,995, filed Oct. 15, 2014; which is a continuation of U.S. patentapplication Ser. No. 13/715,242, filed Dec. 14, 2012, now U.S. Pat. No.8,889,720; which is a continuation of U.S. patent application Ser. No.12/376,238, filed Sep. 3, 2009, now U.S. Pat. No. 8,377,971; which is anational stage application under 35.U.S.C. 371 based on PatentCooperation Treaty Application serial number PCT/US2007/074960, filedAug. 1, 2007; which claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 60/835,194, filed Aug. 3, 2006.

BACKGROUND OF THE INVENTION

Hyperlipidemia and hypercholesterolemia are conditions that have a wellestablished correlation with increased risk of other conditions, such asheart attacks, atherosclerosis, and other deleterious ailments. Thereare numerous agents available for lowering cholesterol and lipid levels,including gemfibrizol, probucol, and, more recently, the “statins” e.g,lovastatin.

Niacin (nicotinic acid and/or nicotinamide), a water soluble B-complexvitamin, is used orally for the treatment of hyperlipidemia. Niacin hasbeen shown to be effective in reducing total plasma cholesterol (C), lowdensity lipoproteins LDL-C and very low density lipoproteintriglycerides (VLDL-triglycerides), all of which are associated withhealth risks. Simultaneously, niacin raises serum levels of high densitylipoproteins (HDL-C), which are considered a “healthy” lipoprotein, inpatients with types II, III, IV, and V hyperlipoproteinemia.

Although the mechanism by which niacin alters lipid profiles has notbeen well defined, its mechanisms of action have been shown to includeinhibition of free fatty acid release from adipose tissue (see Carlson,L. A., Froberg, S. O. and Nye, E. R., Nicotinic acid in the rat. 11.Acute effects of nicotinic acid on plasma, liver, heart, and musclelipids, Acta Med Scand 180: 571-579, 1966), and increased lipoproteinlipase activity (see Priego, J. G., Pina, M., Armijo, M., Sunkel, C. andMaroto, M. L., Action of etofibrate, clofibrate and nicotinic acid onthe metabolism of lipids in normolipemic rats. Short term effects andmethod of action, Arch Farmacol Toxicol 5: 29-42, 1979). More than 30million Americans have elevated blood LDL-C levels. HMG-CoA reductaseinhibitors (statins) are the most widely used class of drugs fortreating patients with elevated levels of LDL-C. Niacin, however, is theonly drug recommended by the American Heart Association for HDLimprovement in primary prevention of cardiovascular diseases in additionto lowering LDL-C. Niacin therapy is not only cost-effective as amonotherapy, but it is also beneficial as a combination therapy becauseit complements the effects of other classes of lipid-lowering drugs.However, niacin is a second or third choice for isolated,hypercholesterolemia because of a high incidence of side effectsassociated with oral niacin therapy. Nevertheless, it has a therapeuticadvantage as a monotherapy when reduction of both LDL-C andtriglycerides are desired, such as for patients with severe combinedhyperlipidemia.

Niacin may also be used in combination with other cholesterol-loweringagents, such as the “statins”, to maximize lipid-lowering activity. Onestudy showed that a niacin/lovastatin combination is highly effective inlowering LDL-C, triglycerides and lipoprotein a[Lp(a)] while retainingniacin's potency in raising HDL-C (Kashyap, M. L., Evans R., Simmons, P.D., Kohler, R. M. and McGoven, M. E., New combination niacin/statinformulation shows pronounced effects on major lipoproteins and welltolerated, J Am Coll Card Suppl. A 35: 326, 2000).

Niacin has been widely used for reducing serum cholesterol levelsbecause it is considered a cost-effective therapy. Daily oral doses of2-3 g niacin in humans reduce levels of total-C and LDL-C by an averageof 20% to 30%, reduce triglyceride levels 35% to 55%, increase HDL-C 20%to 35%, and reduce Lp(a). Niacin also reduces total mortality as well asmortality from coronary artery disease (see The Coronary Drug ProjectResearch Group, JAMA 231: 360-381, 1975; and Canner, P. L., Berge, K.G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J. andFriedewald, W., Fifteen year mortality in Coronary Drug Projectpatients: long-term benefit with niacin, J Am Coll Cardiol 8: 1245-1255,1986.) and it helps to slow or reverse the progression ofatherosclerosis (see Blankenhom, D. H., Nessim, S. A., Johnson, R. L.,Samnarco, M. E., Azen, S. P. and Cashin-Hemphill, L., Beneficial effectsof combined colestipol-niacin therapy on coronary atheroscloerosis andcoronary venous bypass grafts, JAMA 257: 3233-3240, 1987.; andCashin-Hemphill L.; Mack, W. J., Pogoda, J. M., Samnarco, M. E., Azen,S. P. and Blankenhorn, D. H., Beneficial effects of colestipol-niacin oncoronary atherosclerosis. A 4-year follow-up, JAMA 264: 3013-3017,1990).

Unfortunately, oral niacin therapy has side effects that limit itsutility. Although niacin is a vitamin, it must be used in therapeuticdoses to lower cholesterol. At these doses, both immediate-release andsustained-release niacin can have several side effects. The most commonside effect of niacin is flushing, a warm feeling in the skin usuallyassociated with redness and sometimes itching. Flushing is notdangerous, but most patients find it very uncomfortable, which seriouslylimits patient compliance with niacin therapy. Niacin-induced flushingcan be substantially attenuated by pretreatment with cyclooxygenaseinhibitors, suggesting that the vasodilation is caused by aprostaglandin-mediated mechanism (see Carlson, L. A., Nicotinic acid andinhibition of fat mobilizing lipolysis. Present status, of effects onlipid metabolism, Adv Exp Med Biol 109: 225-23 8, 1978).

Liver function tests are always monitored in patients taking niacinsince elevation of serum transaminase levels has been associated withniacin treatment, and sustained-release niacin formulations have beenassociated with more serious liver problems (see McKenney, J. M.,Proctor, J. D., Harris, S., and Chinchili, V. M., A comparison of theefficacy and toxic effects of sustained-vs immediate-release niacin inhypercholesterolemic patients, JAMA 271: 672-777, 1994; and Stafford, R.S., Blumenthal, D. and Pasternak, R. C., Variations in cholesterolmanagement practices of U.S. physicians, J Am Coll Cardiol 29: 139-146,1997). Other known side effects of oral niacin therapy includeactivation of peptic ulcers, gout, and worsening of diabetes control.Accordingly, the safety and efficacy of oral niacin therapy isundermined by the need for careful clinical monitoring and thecompound's side-effect profile.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to substituted pyridines andpharmaceutically acceptable salts thereof that are active against arange of mammalian maladies. In certain embodiments, said pyridines orsalts thereof comprise at the 3-position or 5-position a substituentcomprising a functional group that is substantially anionic atphysiological pH. In certain embodiments, said pyridines or saltsthereof comprise at the 2-position or 6-position a substituentcomprising a functional group that is electron donating to the pyridinering. In certain embodiments, said pyridines or salts thereof compriseat the 5-position a substituent comprising a functional group that issubstantially anionic at physiological pH; and at the 2-position asubstituent comprising a functional group that is electron donating tothe pyridine ring.

Another aspect of the invention relates to a pharmaceutical composition,comprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable excipient.Yet another aspect of the invention relates to a pharmaceuticalcomposition, comprising a compound of the present invention or apharmaceutically acceptable salt thereof; niacin; and a pharmaceuticallyacceptable excipient. Another aspect of the invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; a statinselected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol; and apharmaceutically acceptable excipient. The present invention alsorelates to a pharmaceutical composition, comprising a compound of thepresent invention or a pharmaceutically acceptable salt thereof; niacin;a statin selected from the group consisting of atorvastatin,cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,pravastatin, rosuvastatin, simvastatin, gemcabene, and probucol; and apharmaceutically acceptable excipient.

The present invention also relates to a method of treatinghyperlipidemia, hypercholesterolemia, atherosclerosis, coronary arterydisease, congestive heart failure, cardiovascular disease, hypertension,coronary heart disease, angina, pellagra, Hartnup's syndrome, carcinoidsyndrome, arterial occlusive disease, obesity, hypothyroidism,vasoconstriction, osteoarthritis, rheumatoid arthritis, diabetes,Alzheimer's disease, lipodystrophy, or dyslipidemia, comprising the stepof administering to a mammal in need thereof a therapeutically effectiveamount of a compound or pharmaceutical composition of the presentinvention. Another aspect of the present invention relates to a methodof raising serum high-density lipoprotein (HDL) levels, comprising thestep of administering to a mammal in need thereof a therapeuticallyeffective amount of a compound or pharmaceutical composition of thepresent invention. Yet another aspect of the present invention relatesto a method of lowering serum low-density lipoprotein (LDL) levels,comprising the step of administering to a mammal in need thereof atherapeutically effective amount of a compound or pharmaceuticalcomposition of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts various niacin analogues of the present invention.

FIG. 2 tabulates the effects of various niacin analogues of the presentinvention on PGD2 release and inhibition of HDL uptake.

FIG. 3 depicts various niacin analogues of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described more fully with reference to theaccompanying examples, in which certain preferred embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Overview

One aspect of the invention relates to niacin analogues for use inraising serum HDL levels in mammals. The compounds of the invention haveequal or greater HDL-raising ability than niacin while having less or nopropensity to induce flushing, an undesirable side effect of niacinitself when used in doses sufficient to raise serum HDL levels. Incertain embodiments, key structural features appear to include theplacement of a negatively charged group at a greater distance from thepyridine ring in a sterically constrained trans configuration relativeto the ring and/or the absence of a carbonyl oxygen in the positionanalogous to that occupied by the carboxyl group in niacin.

For example, 4-pyridin-3-yl-but-3-enoic acid (2035) reduces HDL uptakeby Hep-G2 cells, which is an assay that serves as proxy for HDL-raisingactivity, essentially as well as niacin and yet has very much lessability to induce PDG2 release by THP-1 macrophages, which is an assaythat serves as proxy for flush inducing activity (FIG. 1 and Table 1)while the structurally very similar compounds, 2040, 2038, and 2230A(FIG. 1) have no HDL-raising activity, yet are more potent that niacinitself in inducing flushing (Table 1). The results also indicate thatthe HDL-raising activity niacin and therefore of niacin analogs like2235 can be improved by substitutions to the niacin ring in the positionpara to the carboxylate group as illustrated by 2230C (FIG. 1, and Table1). 2030C is niacin with a substitution para to the carboxylate group.The results in Table 1 show this molecule is better than niacin itselfin raising HDL. However it retains the ability to generate flush. Wepropose that an improved niacin analog can be constructed that hasgreater HDL-raising activity than niacin and greatly reduced propensityto generate flush by adding substitutent in the para position of 2230Cto 2035.

COMPOUNDS OF THE INVENTION

In certain embodiments, the present invention relates to a compoundrepresented by structure A, or a pharmaceutically acceptable saltthereof:

wherein

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, alkyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl; or the twoinstances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, or —(CH₂)₆—;

R″ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

n is 1, 2, 3, or 4.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or thetwo instances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl, oraralkyl; or the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₄—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and the twoinstances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH or alkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl; R′represents independently for each occurrence H, alkyl, alkenyl, alkynyl,aryl, heteroaryl, aralkyl, or heteroaralkyl; or the two instances of R′taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or—(CH₂)₆—; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl; thetwo instances of R′ taken together represent —(CH₂)₄—; and R″ representsH or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; and R″ represents Hor alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H oralkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure A or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H; andn is 2.

In certain embodiments, the present invention relates to a compoundrepresented by structure B, or a pharmaceutically acceptable saltthereof:

wherein

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R″ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

m is 1, 2, or 3.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R′represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H; and R″represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H; and R″represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R′ representsindependently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH or alkyl; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H; R″ representsH or alkyl; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H; R″ representsH; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R′ representsindependently for each occurrence H; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R′ representsindependently for each occurrence H; and R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R′ representsindependently for each occurrence H; R″ represents H or alkyl; and m is1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure B or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R′ representsindependently for each occurrence H; R″ represents H; and m is 1.

In certain embodiments, the present invention relates to a compoundrepresented by structure C, or a pharmaceutically acceptable saltthereof:

wherein

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, alkyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl; or the twoinstances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, or —(CH₂)₆—;

R″ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R³ represents independently for each occurrence H, alkyl, alkonyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

n is 1, 2, 3, or 4; and

m is 1, 2, or 3.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or thetwo instances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl, oraralkyl; or the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R³ represents independently for each occurrence H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R³ represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R³represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH or alkyl; and R³ represents independently for each occurrence H oralkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH; and R³ represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H oralkyl; and R³ represents independently for each occurrence H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H; andR³ represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H oralkyl; R³ represents independently for each occurrence H or alkyl; and nis 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H; R³represents independently for each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R³ representsindependently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH or alkyl; R³ represents independently for each occurrence H or alkyl;and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH; R³ represents independently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H oralkyl; R³ represents independently for each occurrence H or alkyl; and mis 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H; R³represents independently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H oralkyl; R³ represents independently for each occurrence H or alkyl; n is2; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H; R³represents independently for each occurrence H; n is 2; and m is 1.

In certain embodiments, the present invention relates to a compoundrepresented by structure D, or a pharmaceutically acceptable saltthereof:

wherein

X represents —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH—CH—,—CH═CHCH₂—, —CH₂CH═CH—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH—, —CH₂CH₂CH═CH—, or

—CH═CHCH═CH—;

Y represents —CO₂R″, —SO₃H, —SO₂NH₂; —B(OH)₂, —PO₃H₂, or 5-tetrazolyl;

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, alkyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl; or the twoinstances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, or —(CH₂)₆—;

R″ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

n is 1, 2, 3, or 4.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; and R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or thetwo instances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl, oraralkyl; or the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and the twoinstances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH or alkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl; R′represents independently for each occurrence H, alkyl, alkenyl, alkynyl,aryl, heteroaryl, aralkyl, or heteroaralkyl; or the two instances of R′taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or—(CH₂)₆—; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl; thetwo instances of R′ taken together represent —(CH₂)₄—; and R″ representsH or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; and R″ represents Hor alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H oralkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R″ represents H; andn is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H; and the two instances of R′ taken togetherrepresent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H; the two instances of R′ taken together represent—(CH₂)₄—; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; R″ represents H or alkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H, or alkyl; R′ represents independently for each occurrenceH, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;or the two instances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H, or alkyl; the two instances of R′ taken together represent—(CH₂)₄—; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; the two instances of R′ taken together represent —(CH₂)₄—;and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; the two instances of R′ taken together represent —(CH₂)₄—;R″ represents H or alkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure D or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; the two instances of R′ taken together represent —(CH₂)₄—;R″ represents H; and n is 2.

In certain embodiments, the present invention relates to a compoundrepresented by structure E, or a pharmaceutically acceptable saltthereof:

wherein

X represents —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—,—CH═CHCH₂—, —CH₂CH═CH—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—, or

—CH═CHCH═CH—;

Y represents —CO₂R″, —SO₃H, —SO₂NH₂; —B(OH)₂, —PO₃H₂, or 5-tetrazolyl;

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, alkyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl;

R″ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

n is 1, 2, 3, or 4.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; and R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl, oraralkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R″ representsH or alkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl; R′represents independently for each occurrence H, alkyl, alkenyl, alkynyl,aryl, heteroaryl, aralkyl, or heteroaralkyl; and R″ represents H oralkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H; R″ represents H or alkyl; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure E or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R represents independently for eachoccurrence H, or alkyl; R′ represents independently for each occurrenceH, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;and R″ represents H or alkyl.

In certain embodiments, the present invention relates to a compoundrepresented by structure F, or a pharmaceutically acceptable saltthereof:

wherein

X represents —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—,—CH═CHCH₂—, —CH₂CH═CH—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—, or

—CH═CHCH═CH—;

Y represents —CO₂R″, —SO₃H, —SO₂NH₂; —B(OH)₂, —PO₃H₂, or 5-tetrazolyl;

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl; and

R″ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; and R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R″ represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R″represents H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H, alkyl, fluoride, chloride, bromide, nitro, cyano,sulfonic acid, hydroxyl, alkoxyl, thiol, alkylthio, formyl, acyl,formyloxy, acyloxy, formylthio, acylthio, amino, alkylamino,formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; R″ represents H; R represents independentlyfor each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure F or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein Y represents —CO₂R″; and R″ represents H or alkyl.

In certain embodiments, the present invention relates to a compoundrepresented by structure G, or a pharmaceutically acceptable saltthereof:

wherein

Y represents —SO₃H, —SO₂NH₂; —B(OH)₂, —PO₃H₂, or 5-tetrazolyl;

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, alkyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl; or the twoinstances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, or —(CH₂)₆—; and

n is 1, 2, 3, or 4.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence IT, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or thetwo instances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl, oraralkyl; or the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure C or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and the twoinstances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure G or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; and n is 2.

In certain embodiments, the present invention relates to a compoundrepresented by structure H, or a pharmaceutically acceptable saltthereof:

wherein

Y represents —SO₃H, —SO₂NH₂; —B(OH)₂, —PO₃H₂, or 5-tetrazolyl;

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

m is 1, 2, or 3.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R′represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure H or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R′ representsindependently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to a compoundrepresented by structure I, or a pharmaceutically acceptable saltthereof:

wherein

Y represents —SO₃H, —SO₂NH₂; —B(OH)₂, —PO₃H₂, or 5-tetrazolyl;

R represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride, chloride,bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl;

R′ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, alkyloxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl; or the twoinstances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, or —(CH₂)₆—;

R³ represents independently for each occurrence H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

n is 1, 2, 3, or 4; and

m is 1, 2, or 3.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, alkyl,fluoride, chloride, bromide, nitro, cyano, sulfonic acid, hydroxyl,alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy, formylthio,acylthio, amino, alkylamino, formylamino, acylamino, or carboxylate.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H, or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or thetwo instances of R′ taken together represent —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R′ represents independently for each occurrence H, alkyl, oraralkyl; or the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein the two instances of R′ taken together represent —(CH₂)₄—.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R³ represents independently for each occurrence H or alkyl.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R³ represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein n is 2.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; and R³represents independently for each occurrence H.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; R³ representsindependently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R³ representsindependently for each occurrence H; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R³ representsindependently for each occurrence H or alkyl; n is 2; and m is 1.

In certain embodiments, the present invention relates to any of theaforementioned compounds represented by structure I or thepharmaceutically acceptable salts thereof and the attendant limitations,wherein R represents independently for each occurrence H; the twoinstances of R′ taken together represent —(CH₂)₄—; R³ representsindependently for each occurrence H; n is 2; and m is 1.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; a statinselected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to any of theaforementioned pharmaceutical compositions and the attendantlimitations, wherein said statin is lovastatin or atorvastatin.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; a glitazoneselected from the group consisting of troglitazone, rosiglitazone, andpioglitazone; and a pharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; aglitazone selected from the group consisting of troglitazone,rosiglitazone, and pioglitazone; and a pharmaceutically acceptableexcipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; a fibrateselected from the group consisting of fenofibrate and bezafibrate; and apharmaceutically acceptable excipient.

In certain embodiments, the present invention relates to apharmaceutical composition, comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof; niacin; afibrate selected from the group consisting of fenofibrate andbezafibrate; and a pharmaceutically acceptable excipient.

METHODS OF THE INVENTION

A method of treating hyperlipidemia, hypercholesterolemia,atherosclerosis, coronary artery disease, congestive heart failure,cardiovascular disease, hypertension, coronary heart disease, angina,pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusivedisease, obesity, hypothyroidism, vasoconstriction, osteoarthritis,rheumatoid arthritis, diabetes, Alzheimer's disease, lipodystrophy, ordyslipidemia, comprising the step of:

administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention.

A method of treating hyperlipidemia, comprising the step of:

administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention.

A method of raising serum high-density lipoprotein (HDL) levels,comprising the step of:

administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention.

A method of lowering serum low-density lipoprotein (LDL) levels,comprising the step of:

administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention.

A method of lowering serum lipoprotein (a) (Lp(a)) levels, comprisingthe step of:

administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention.

A method of treating hyperlipidemia, hypercholesterolemia,atherosclerosis, coronary artery disease, congestive heart failure,cardiovascular disease, hypertension, coronary heart disease, angina,pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusivedisease, obesity, hypothyroidism, vasoconstriction, osteoarthritis,rheumatoid arthritis, diabetes, Alzheimer's disease, lipodystrophy, ordyslipidemia, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin.

A method of treating hyperlipidemia, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin.

A method of raising serum high-density lipoprotein (HDL) levels in amammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin.

A method of lowering serum low-density lipoprotein (LDL) levels in amammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin.

A method of lowering serum lipoprotein (a) (Lp(a)) levels in a mammal,comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of niacin.

A method of treating hyperlipidemia, hypercholesterolemia,atherosclerosis, coronary artery disease, congestive heart failure,cardiovascular disease, hypertension, coronary heart disease, angina,pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusivedisease, obesity, hypothyroidism, vasoconstriction, osteoarthritis,rheumatoid arthritis, diabetes, Alzheimer's disease, lipodystrophy, ordyslipidemia, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, andprobucol.

A method of treating hyperlipidemia, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, andprobucol.

A method of raising serum high-density lipoprotein (HDL) levels in amammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, andprobucol.

A method of lowering serum low-density lipoprotein (LDL) levels in amammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, andprobucol.

A method of lowering serum lipoprotein (a) (Lp(a)) levels in a mammal,comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; and a therapeuticallyeffective amount of a statin selected from the group consisting ofatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, andprobucol.

A method of treating hyperlipidemia, hypercholesterolemia,atherosclerosis, coronary artery disease, congestive heart failure,cardiovascular disease, hypertension, coronary heart disease, angina,pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusivedisease, obesity, hypothyroidism, vasoconstriction, osteoarthritis,rheumatoid arthritis, diabetes, Alzheimer's disease, lipodystrophy, ordyslipidemia, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol.

A method of treating hyperlipidemia, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol.

A method of raising serum high-density lipoprotein (HDL) levels in amammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol.

A method of lowering serum low-density lipoprotein (LDL) levels in amammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol.

A method of lowering serum lipoprotein (a) (Lp(a)) levels in a mammal,comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention; a therapeuticallyeffective amount of niacin; and a therapeutically effective amount of astatin selected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, simvastatin, gemcabene, and probucol.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidstatin is lovastatin or atorvastatin.

A method of treating diabetes in a mammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof; and a glitazone selected from the groupconsisting of troglitazone, rosiglitazone, and pioglitazone.

A method of treating diabetes in a mammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof; niacin; and a glitazone selected from the groupconsisting of troglitazone, rosiglitazone, and pioglitazone.

A method of treating diabetes in a mammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof; and a fibrate selected from the groupconsisting of fenofibrate and bezafibrate.

A method of treating diabetes in a mammal, comprising the step of:

co-administering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt thereof; niacin; and a fibrate selected from the groupconsisting of fenofibrate and bezafibrate.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidmammal is a primate, bovine, ovine, rodent, equine, canine, or feline.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidmammal is a human.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered by inhalation.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered orally.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered intravenously.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered sublingually.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered ocularly.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered transdermally.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered rectally.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered vaginally.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered topically.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered intramuscularly.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered subcutaneously.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered buccally.

In certain embodiments, the present invention relates to any of theaforementioned methods and the attendant limitations, wherein saidcompound or compounds are administered nasally.

DEFINITIONS

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The terms “co-administration” and “co-administering” refer to bothconcurrent administration (administration of two or more therapeuticagents at the same time) and time varied administration (administrationof one or more therapeutic agents at a time different from that of theadministration of an additional therapeutic agent or agents), as long asthe therapeutic agents are present in the patient to some extent at thesame time.

The term “electron-withdrawing group” is recognized in the art, anddenotes the tendency of a substituent to attract valence electrons fromneighboring atoms, i.e., the substituent is electronegative with respectto neighboring atoms. A quantification of the level ofelectron-withdrawing capability is given by the Hammett sigma (σ)constant. This well known constant is described in many references, forinstance, J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1977 edition) pp. 251-259. The Hammett constantvalues are generally negative for electron donating groups (σ[P]=−0.66for NH₂) and positive for electron withdrawing groups (σ[P]=0.78 for anitro group), σ[P] indicating para substitution. Exemplaryelectron-withdrawing groups include nitro, acyl, formyl, sulfonyl,trifluoromethyl, cyano, chloride, and the like. Exemplaryelectron-donating groups include amino, methoxy, and the like.

The term “aliphatic” is an art-recognized term and includes linear,branched, and cyclic alkanes, alkenes, or alkynes. In certainembodiments, aliphatic groups in the present invention are linear orbranched and have from 1 to about 20 carbon atoms.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and alternatively about 5, 6 or 7 carbons in the ringstructure.

Unless the number of carbons is otherwise specified, “lower alkyl”refers to an alkyl group, as defined above, but having from one to tencarbons, alternatively from one to about six carbon atoms in itsbackbone structure. Likewise, “lower alkonyl” and “lower alkynyl” havesimilar chain lengths.

The term “bicyclo-ring” as used herein refers to a bridged ring system,such as a quinuclidine (shown below).

The term “aralkyl” is art-recognized, and includes alkyl groupssubstituted with an aryl group (e.g., an aromatic or heteroaromaticgroup).

The terms “alkenyl” and “alkynyl” are art-recognized, and includeunsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “heteroatom” is art-recognized, and includes an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium, andalternatively oxygen, nitrogen or sulfur.

The term “aryl” is art-recognized, and includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, naphthalene, anthracene, pyrene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “heteroaryl” or “heteroaromatics.” The aromatic ring maybe substituted at one or more ring positions with such substituents asdescribed above, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl,aromatic or heteroaromatic moieties, fluoroalkyl (such astrifluromethyl), cyano, or the like. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (the rings are “fusedrings”) wherein at least one of the rings is aromatic, e.g., the othercyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls.

The terms ortho (o-), meta (m-) and para (p-) are art-recognized andapply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. Forexample, the names 1,2-dimethylbenzene, ortho-dimethylbenzene ando-dimethylbenzene are synonymous.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized,and include 3- to about 10-membered ring structures, such as 3- to about7-membered rings, whose ring structures include one to four heteroatoms.Heterocycles may also be polycycles. Heterocyclyl groups include, forexample, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene,xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine,furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole,piperidine, piperazine, morpholine, lactones, lactams such asazetidinones and pyrrolidinones, sultams, sultones, and the like. Theheterocyclic ring may be substituted at one or more positions with suchsubstituents as described above, as for example, halogen, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, fluoroalkyl (such astrifluromethyl), cyano, or the like.

The terms “polycyclyl” and “polycyclic group” are art-recognized, andinclude structures with two or more rings (e.g., cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which twoor more carbons are common to two adjoining rings, e.g., the rings are“fused rings”. Rings that are joined through non-adjacent atoms, e.g.,three or more atoms are common to both rings, are termed “bridged”rings. Each of the rings of the polycycle may be substituted with suchsubstituents as described above, as for example, halogen, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, fluoroalkyl (such astrifluromethyl), cyano, or the like.

The term “carbocycle” is art recognized and includes an aromatic ornon-aromatic ring in which each atom of the ring is carbon. The flowingart-recognized terms have the following meanings: “nitro” means —NO₂;the term “halogen” designates —F, —Cl, —Br or —I; the term “sulfhydryl”means —SH; the term “hydroxyl” means —OH; and the term “sulfonyl” means—SO₂ ⁻.

The terms “amine” and “amino” are art-recognized and include bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R61, or R50 and R51, taken together withthe N atom to which they are attached complete a heterocycle having from4 to 8 atoms in the ring structure; R61 represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In certain embodiments, only oneof R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogentogether do not form an imide. In other embodiments, R50 and R51 (andoptionally R52) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R61. Thus, the term “alkylamine” includes anamine group, as defined above, having a substituted or unsubstitutedalkyl attached thereto, i.e., at least one of R50 and R51 is an alkylgroup.

The term “acylamino” is art-recognized and includes a moiety that may berepresented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are as definedabove.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of theamide in the present invention will not include amides which may beunstable.

The term “alkylthio” is art recognized and includes an alkyl group, asdefined above, having a sulfur radical attached thereto. In certainembodiments, the “alkylthio” moiety is represented by one of —S-alkyl,—S-alkenyl, —S-alkynyl, and —S—(CH₂)_(m)—R61, wherein m and R61 aredefined above. Representative alkylthio groups include methylthio,ethylthio, and the like.

The term “carbonyl” is art recognized and includes such moieties as maybe represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61 or apharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R61, where m and R61 are defined above. WhereX50 is an oxygen and R55 is not hydrogen, the formula represents an“ester”. Where X50 is an oxygen, and R55 is as first defined above, themoiety is referred to herein as a carboxyl group, and particularly whenR55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50is an oxygen, and R56 is hydrogen, the formula represents a “formate”.In general, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiocarbonyl” group. Where X50 is asulfur and R55 or R56 is not hydrogen, the formula represents a“thioester.” Where X50 is a sulfur and R55 is hydrogen, the formularepresents a “thiocarboxylic acid.” Where X50 is a sulfur and R56 ishydrogen, the formula represents a “thioformate.” On the other hand,where X50 is a bond, and R55 is not hydrogen, the above formularepresents a “ketone” group. Where X50 is a bond, and R55 is hydrogen,the above formula represents an “aldehyde” group.

The terms “oxime” and “oxime ether” are art-recognized and refer tomoieties that may be represented by the general formula:

wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, or —(CH₂)_(m)—R61. The moiety is an “oxime” when R representsindependently for each occurrence H; and it is an “oxime ether” when Ris alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or—(CH₂)_(m)—R61.

The terms “alkoxyl” or “alkoxy” are art recognized and include an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R61, where m and R61 are described above.

The term “sulfonate” is art recognized and includes a moiety that may berepresented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfate” is art recognized and includes a moiety that may berepresented by the general formula:

in which R57 is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that maybe represented by the general formula:

in which R50 and R56 are as defined above.

The term “sulfamoyl” is art-recognized and includes a moiety that may berepresented by the general formula:

in which R50 and R51 are as defined above.

The term “sulfonyl” is art recognized and includes a moiety that may berepresented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “sulfoxido” is art recognized and includes a moiety that may berepresented by the general formula:

in which R58 is defined above.

The term “phosphoryl” is art-recognized and may in general berepresented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl may be represented by thegeneral formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N. When Q50 is S, the phosphoryl moiety is a“phosphorothioate”.

The term “phosphoramidite” is art recognized and includes moietiesrepresented by the general formulas:

wherein Q51, R50, R51 and R59 are as defined above.

The term “phosphonamidite” is art recognized and includes moietiesrepresented by the general formulas:

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents alower alkyl or an aryl.

The term “selenoalkyl” is art-recognized and refers to an alkyl grouphaving a substituted seleno group attached thereto. Exemplary“selenoethers” which may be substituted on the alkyl are selected fromone of —Se-alkyl, —Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R61, m andR61 being defined above.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,polymers of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

Analogous substitutions may be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g. alkyl, m, n, etc., when itoccurs more than once in any structure, is intended to be independent ofits definition elsewhere in the same structure unless otherwiseindicated expressly or by the context.

For purposes of the invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the compounds described above, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,e.g., those targeted for buccal, sublingual, and systemic absorption,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscular,intravenous or epidural injection as, for example, a sterile solution orsuspension, or sustained-release formulation; (3) topical application,for example, as a cream, ointment, or a controlled-release patch orspray applied to the skin; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar, (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia, or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.(See, for example, Berge et al., supra)

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants,such as glycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds andsurfactants, such as poloxamer and sodium lauryl sulfate; (7) wettingagents, such as, cetyl alcohol, glycerol monostearate, and non-ionicsurfactants; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, zinc stearate, sodiumstearate, stearic acid, and mixtures thereof; (10) coloring agents; and(11) controlled-release agents, such as crospovidone or ethyl cellulose.In the case of capsules, tablets and pills, the pharmaceuticalcompositions may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-shelledgelatin capsules using such excipients as lactose or milk sugars, aswell as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable non-irritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants, such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption, such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This result may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form is accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers, such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, administration by injection, infusion orinhalation; topical by lotion or ointment; and rectal by suppositories.Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein mean modes of administration other than enteral andtopical administration, usually by injection, and include, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

Compounds may be administered to humans and other animals for therapy byany suitable route of administration, including orally, nasally, as by,for example, a spray, rectally, intravaginally, parenterally,intracisternally and topically, as by powders, ointments or drops,including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient, when used for the indicated analgesic effects,will range from about 0.0001 to about 100 mg per kilogram of body weightper day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The compounds according to the invention may be formulated foradministration in any convenient way for use in human or veterinarymedicine, by analogy with other pharmaceuticals.

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the subject compounds, as described above,formulated together with one or more pharmaceutically acceptablecarriers (additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscularor intravenous injection as, for example, a sterile solution orsuspension; (3) topical application, for example, as a cream, ointmentor spray applied to the skin, lungs, or mucous membranes; or (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or(8) nasally.

The term “treatment” is intended to encompass also prophylaxis, therapyand cure.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals, such as equines,cattle, swine and sheep; and poultry and pets in general.

The compound of the invention can be administered as such or inadmixtures with pharmaceutically acceptable carriers and can also beadministered in conjunction with antimicrobial agents such aspenicillins, cephalosporins, aminoglycosides and glycopeptides.Conjunctive therapy, thus includes sequential, simultaneous and separateadministration of the active compound in a way that the therapeuticaleffects of the first administered one is not entirely disappeared whenthe subsequent is administered.

Micelles

Microemulsification technology improves bioavailability of somelipophilic (water insoluble) pharmaceutical agents. Examples includeTrimetrine (Dordunoo, S. K., et al., Drug Development and IndustrialPharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., JPharm Sci 80(7), 712-714, 1991). Among other things, microemulsificationprovides enhanced bioavailability by preferentially directing absorptionto the lymphatic system instead of the circulatory system, which therebybypasses the liver, and prevents destruction of the compounds in thehepatobiliary circulation.

While all suitable amphiphilic carriers are contemplated, the presentlypreferred carriers are generally those that haveGenerally-Recognized-as-Safe (GRAS) status, and that can both solubilizethe compound of the present invention and microemulsify it at a laterstage when the solution comes into a contact with a complex water phase(such as one found in human gastro-intestinal tract). Usually,amphiphilic ingredients that satisfy these requirements have HLB(hydrophilic to lipophilic balance) values of 2-20, and their structurescontain straight chain aliphatic radicals in the range of C-6 to C-20.Examples are polyethylene-glycolized fatty glycerides and polyethyleneglycols.

Commercially available amphiphilic carriers are particularlycontemplated, including Gelucire-series, Labrafil, Labrasol, orLauroglycol (all manufactured and distributed by Gattefosse Corporation,Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurateand di-laurate, Lecithin, Polysorbate 80, etc (produced and distributedby a number of companies in USA and worldwide).

Polymers

Hydrophilic polymers suitable for use in the present invention are thosewhich are readily water-soluble, can be covalently attached to avesicle-forming lipid, and which are tolerated in vivo without toxiceffects (i.e., are biocompatible). Suitable polymers includepolyethylene glycol (PEG), polylactic (also termed polylactide),polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolicacid copolymer, and polyvinyl alcohol. Preferred polymers are thosehaving a molecular weight of from about 100 or 120 Daltons up to about5,000 or 10,000 Daltons, and more preferably from about 300 Daltons toabout 5,000 Daltons. In a particularly preferred embodiment, the polymeris polyethyleneglycol having a molecular weight of from about 100 toabout 5,000 Daltons, and more preferably having a molecular weight offrom about 300 to about 5,000 Daltons. In a particularly preferredembodiment, the polymer is polyethyleneglycol of 750 Daltons (PEG(750)).Polymers may also be defined by the number of monomers therein; apreferred embodiment of the present invention utilizes polymers of atleast about three monomers, such PEG polymers consisting of threemonomers (approximately 150 Daltons).

Other hydrophilic polymers which may be suitable for use in the presentinvention include polyvinylpyrrolidone, polymethoxazoline,polyethyloxazoline, polyhydroxypropyl methacrylamide,polymethacrylamide, polydimethylacrylamide, and derivatized cellulosessuch as hydroxymethylcellulose or hydroxyethylcellulose.

In certain embodiments, a formulation of the present invention comprisesa biocompatible polymer selected from the group consisting ofpolyamides, polycarbonates, polyalkylenes, polymers of acrylic andmethacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes,polyurethanes and co-polymers thereof, celluloses, polypropylene,polyethylenes, polystyrene, polymers of lactic acid and glycolic acid,polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid),poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronicacids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.

Cyclodextrins

Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8glucose units, designated by the Greek letters alpha, beta and gamma,respectively. The glucose units are linked by alpha-1,4-glucosidicbonds. As a consequence of the chair conformation of the sugar units,all secondary hydroxyl groups (at C-2, C-3) are located on one side ofthe ring, while all the primary hydroxyl groups at C-6 are situated onthe other side. As a result, the external faces are hydrophilic, makingthe cyclodextrins water-soluble. In contrast, the cavities of thecyclodextrins are hydrophobic, since they are lined by the hydrogen ofatoms C-3 and C-5, and by ether-like oxygens. These matrices allowcomplexation with a variety of relatively hydrophobic compounds,including, for instance, steroid compounds such as 17-beta-estradiol(see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38:1-3-113(1994)). The complexation takes place by Van der Waals interactions andby hydrogen bond formation. For a general review of the chemistry ofcyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822(1994).

The physico-chemical properties of the cyclodextrin derivatives dependstrongly on the kind and the degree of substitution. For example, theirsolubility in water ranges from insoluble (e.g.,triacetyl-beta-cyclodextrin) to 147% soluble (w/v)(G-2-beta-cyclodextrin). In addition, they are soluble in many organicsolvents. The properties of the cyclodextrins enable the control oversolubility of various formulation components by increasing or decreasingtheir solubility.

Numerous cyclodextrins and methods for their preparation have beendescribed. For example, Parmeter (I), et al. (U.S. Pat. No. 3,453,259;incorporated by reference) and Gramera, et al. (U.S. Pat. No. 3,459,731;incorporated by reference) described electroneutral cyclodextrins. Otherderivatives include cyclodextrins with cationic properties [Parmeter(II), U.S. Pat. No. 3,453,257; incorporated by reference], insolublecrosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788; incorporatedby reference), and cyclodextrins with anionic properties [Parmeter(III), U.S. Pat. No. 3,426,011; incorporated by reference]. Among thecyclodextrin derivatives with anionic properties, carboxylic acids,phosphorous acids, phosphinous acids, phosphonic acids, phosphoricacids, thiophosphonic acids, thiosulphinic acids, and sulfonic acidshave been appended to the parent cyclodextrin [see, Parmeter (III),supra]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have beendescribed by Stella, et al. (U.S. Pat. No. 5,134,127; incorporated byreference).

Liposomes

Liposomes consist of at least one lipid bilayer membrane enclosing anaqueous internal compartment. Liposomes may be characterized by membranetype and by size. Small unilamellar vesicles (SUVs) have a singlemembrane and typically range between 0.02 and 0.05 μm in diameter, largeunilamellar vesicles (LUVS) are typically larger than 0.05 μmOligolamellar large vesicles and multilamellar vesicles have multiple,usually concentric, membrane layers and are typically larger than 0.1μm. Liposomes with several nonconcentric membranes, i.e., severalsmaller vesicles contained within a larger vesicle, are termedmultivesicular vesicles.

One aspect of the present invention relates to formulations comprisingliposomes containing a compound of the present invention, where theliposome membrane is formulated to provide a liposome with increasedcarrying capacity. Alternatively or in addition, the compound of thepresent invention may be contained within, or adsorbed onto, theliposome bilayer of the liposome. The compound of the present inventionmay be aggregated with a lipid surfactant and carried within theliposome's internal space; in these cases, the liposome membrane isformulated to resist the disruptive effects of the activeagent-surfactant aggregate.

According to one embodiment of the present invention, the lipid bilayerof a liposome contains lipids derivatized with polyethylene glycol(PEG), such that the PEG chains extend from the inner surface of thelipid bilayer into the interior space encapsulated by the liposome, andextend from the exterior of the lipid bilayer into the surroundingenvironment.

Active agents contained within liposomes of the present invention are insolubilized form. Aggregates of surfactant and active agent (such asemulsions or micelles containing the active agent of interest) may beentrapped within the interior space of liposomes according to thepresent invention. A surfactant acts to disperse and solubilize theactive agent, and may be selected from any suitable aliphatic,cycloaliphatic or aromatic surfactant, including but not limited tobiocompatible lysophosphatidylcholines (LPCs) of varying chain lengths(for example, from about C14 to about C20). Polymer-derivatized lipidssuch as PEG-lipids may also be utilized for micelle formation as theywill act to inhibit micelle/membrane fusion, and as the addition of apolymer to surfactant molecules decreases the CMC of the surfactant andaids in micelle formation. Preferred are surfactants with CMCs in themicromolar range; higher CMC surfactants may be utilized to preparemicelles entrapped within liposomes of the present invention, however,micelle surfactant monomers could affect liposome bilayer stability andwould be a factor in designing a liposome of a desired stability.

Liposomes useful in the present invention may be prepared by any of avariety of techniques that are known in the art. See, e.g., U.S. Pat.No. 4,235,871; Published PCT applications WO 96/14057; New RRC,Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104;Lasic D D, Liposomes from physics to applications, Elsevier SciencePublishers BV, Amsterdam, 1993.

For example, liposomes useful in the present invention may be preparedby diffusing a lipid derivatized with a hydrophilic polymer intopreformed liposomes, such as by exposing preformed liposomes to micellescomposed of lipid-grafted polymers, at lipid concentrationscorresponding to the final mole percent of derivatized lipid which isdesired in the liposome. Liposomes containing a hydrophilic polymer canalso be formed by homogenization, lipid-field hydration, or extrusiontechniques, as are known in the art.

In one aspect of the present invention, the liposomes have substantiallyhomogeneous sizes in a selected size range. One effective sizing methodinvolves extruding an aqueous suspension of the liposomes through aseries of polycarbonate membranes having a selected uniform pore size;the pore size of the membrane will correspond roughly with the largestsizes of liposomes produced by extrusion through that membrane. Seee.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).

Release Modifiers

The release characteristics of a formulation of the present inventiondepend on the encapsulating material, the concentration of encapsulateddrug, and the presence of release modifiers. For example, release can bemanipulated to be pH dependent using a pH sensitive coating thatreleases only at a low pH, as in the stomach, or a higher pH, as in theintestine. An enteric coating can be used to prevent release fromoccurring until after passage through the stomach. Multiple coatings ormixtures of cyanamide encapsulated in different materials can be used toobtain an initial release in the stomach, followed by later release inthe intestine. Release can also be manipulated by inclusion of salts orpore forming agents, which can increase water uptake or release of drugby diffusion from the capsule. Excipients which modify the solubility ofthe drug can also be used to control the release rate. Agents whichenhance degradation of the matrix or release from the matrix can also beincorporated. They can be added to the drug, added as a separate phase(i.e., as particulates), or can be co-dissolved in the polymer phasedepending on the compound. In all cases the amount should be between 0.1and thirty percent (w/w polymer). Types of degradation enhancers includeinorganic salts, such as ammonium sulfate and ammonium chloride, organicacids, such as citric acid, benzoic acid, and ascorbic acid, inorganicbases, such as sodium carbonate, potassium carbonate, calcium carbonate,zinc carbonate, and zinc hydroxide, and organic bases, such as protaminesulfate, spermine, choline, ethanolamine, diethanolamine, andtriethanolamine and surfactants, such as Tween® and Pluronic®. Poreforming agents which add microstructure to the matrices (i.e., watersoluble compounds, such as inorganic salts and sugars) are added asparticulates. The range should be between one and thirty percent (w/wpolymer).

Uptake can also be manipulated by altering residence time of theparticles in the gut. This can be achieved, for example, by coating theparticle with, or selecting as the encapsulating material, a mucosaladhesive polymer. Examples include most polymers with free carboxylgroups, such as chitosan, celluloses, and especially polyacrylates (asused herein, polyacrylates refers to polymers including acrylate groupsand modified acrylate groups such as cyanoacrylates and methacrylates).

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Synthesis of 4-pyridin-3-yl-but-3-enoic acid (Compound 2035)

The target compound 4-pyridin-3-yl-but-3-enoic acid (Compound 2035) wasprepared by two steps starting from the commercial available3-Pyridinecarboxaldehyde. Reaction of this aldehyde with ethyl acrylateand triphenylphosphine in a sealed tube for 4 hr at 140° C. gave ethyl4-pyridin-3-yl-3-butenoate in a 55% yield. Kirby, Anthony J.; Walwyn,David R. Effective molarities for intramolecular hydride transfer.Reduction by 1,4-dihydropyridines of the neighboring α-ketoester group.Gazzetta Chimica Italiana (1987), 117(11), 667-80. This reaction is aself-priming Wittig reaction and the yield was not optimized. GilbertStork, R. A. Kretchmer, R. H. Schlessinger. The Stereospecific TotalSynthesis of dl-Lycopodine. J. Am. Chem. Soc. (1968), 90, 1647.Hydrolysis of the ester using the routine condition and the subsequentpurification with preparative HPLC afforded the target compound 2035with almost quantitative yield.

Example 2 Synthesis of4-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-but-3 enoic acid (Compound2035B)

The target compound4-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-but-3-enoic acid (Compound2035B) was prepared by four steps starting from the commercial available6-[2-(Pyrrolidin-1-yl)ethyl]pyridine 1. Firstly, reduction of acid 1with lithium aluminum hydride was performed in THF at 0° C. for 4 hr,providing alcohol 2 in a yield of 80%. Compound 2 was then oxidized tothe corresponding aldehyde 3 using Manganese (IV) oxides as the reagentin a yield of 60%. Delarue, S.; Girault, S.; Maes, L.; Debreu-Fontaine,M.-A.; Labacid, M.; Grellier, P.; Sergheraert, C. Synthesis and in Vitroand in Vivo Antimalarial Activity of New 4-Anilinoquinolines. J. Med.Chem. 2001, 44(17), 2827-2833. Reaction of this aldehyde with ethylacrylate and triphenylphosphine in a sealed tube for 4 hr at 140° C.gave ethyl 4-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-but-3-enoicacid, which on subsequent hydrolysis using the routine conditionfollowed by purification with preparative HPLC afforded the targetcompound 2035B as a TFA salt with a 4% yield. Kirby, Anthony J.; Walwyn,David R. Effective molarities for intramolecular hydride transfer.Reduction by 1,4-dihydropyridines of the neighboring α-ketoester group.Gazzetta Chimica Italiana (1987), 117(11), 667-80. However, the yieldswere not optimized.

Example 3 Synthesis of Compound 2035C

Example 4 Synthesis of Compound 2035D

Example 5 Synthesis of Compound 2805

Example 6 Synthesis of Compound 2805B

Example 7 Synthesis of Compound 2805C

Example 8 Synthesis of Compound 2805D

Example 9 Outline of Hep G2 Cell Assay Experimental Protocol

Split HepG2 cells in 24 well plates 2-3 days prior to niacin treatment,0.5 mL complete DMEM media is added per well

Cells were pre-incubated with niacin (1 mM) for 24˜48 h

Wash HepG2 cells 3 times with PBS

Incubate HepG2 cells in 250 mL medium C(DMEM containing 5 mg/mL fattyacid free BSA), containing ¹²⁵I-labelled HDL (5˜10 mg/mL withspecificity of 300-500 cpm/ng HDL protein. For 16 h

Aspirate the media and wash the cells with 0.5 mL of 0.1 mg/mL BSA-PBStwice, and with PBS twice

Cells were digested in 250 mL of 1 N NaOH at room temperature overnight

100 mL of cell lysate was used for gamma-counting

100 mL of cell lysate was used for protein assay by BCA method

HDL uptake activity is expressed as “cpm of ¹²⁵I-HDL uptake/mg of cellprotein.

Example 10 Outline of PGD2 Assay Experimental Protocol

THP-1 cells were grown in RPMI complete media

2×10⁶ cells/well in 24 well flask were seeded in serum free mediacontaining 16 nM/mL of PMA. Cells were allowed to differentiate intomacrophages for 12 hours

The media was replaced with complete RPMI media and incubation continuedfor 5 hours

After incubation, media was aspirated and cells were treated with niacinand niacin analogs in 1 mL of serum free RPMI media.

Incubated for 30 min. 100 mL of media was collected, PGD2 secreted wasderivitized into stable MOX derivative.

PGD2 in the sample was assayed by using PGD2 assay kit from Caymanchemicals.

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. patent application publications citedherein are hereby incorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A method of reducing plasma triglycerides, comprising thestep of: administering to a mammal in need thereof a therapeuticallyeffective amount of a compound represented by structure A, or apharmaceutically acceptable salt thereof, thereby reducing plasmatriglycerides in the mammal:

wherein R represents independently for each occurrence H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, fluoride,chloride, bromide, iodide, nitro, cyano, sulfonic acid, alkylsulfoxyl,arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl, formyloxy,acyloxy, formylthio, acylthio, amino, alkylamino, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,alkynylamino, formylamino, acylamino, carboxylate, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,heteroaralkyloxycarbonyl, carboxamido, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl; R′ represents independently for eachoccurrence H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, formyl, acyl,amino, alkylamino, arylamino, heteroarylamino, aralkylamino,heteroaralkylamino, alkenylamino, alkynylamino, formylamino, acylamino,alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,aralkyloxycarbonyl, heteroaralkyloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, orheteroaralkylaminocarbonyl; or the two instances of R′ taken togetherrepresent —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—; R″represents independently for each occurrence H, alkyl, alkenyl, alkynyl,aryl, heteroaryl, aralkyl, or heteroaralkyl; and n is 1, 2, 3, or
 4. 2.The method of claim 1, wherein R represents independently for eachoccurrence H, fluoride, chloride, cyano, methyl, or ethyl.
 3. The methodof claim 1, wherein R represents independently for each occurrence H. 4.The method of claim 1, wherein R′ represents independently for eachoccurrence H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; or the two instances of R′ taken together represent—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.
 5. The method ofclaim 1, wherein the two instances of R′ taken together represent—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, or —(CH₂)₆—.
 6. The method ofclaim 1, wherein the two instances of R′ taken together represent—(CH₂)₄—.
 7. The method of claim 1, wherein R″ represents H, alkyl,aryl, or aralkyl.
 8. The method of claim 1, wherein R″ represents H. 9.The method of claim 1, wherein n is
 2. 10. The method of claim 1,wherein R represents independently for each occurrence H; and n is 2.11. The method of claim 1, wherein R represents independently for eachoccurrence H; and the two instances of R′ taken together represent—(CH₂)₄—.
 12. The method of claim 1, wherein R represents independentlyfor each occurrence H; and R″ represents H or alkyl.
 13. The method ofclaim 1, wherein the two instances of R′ taken together represent—(CH₂)₄—; and n is
 2. 14. The method of claim 1, wherein R representsindependently for each occurrence H; the two instances of R′ takentogether represent —(CH₂)₄—; and n is
 2. 15. The method of claim 1,wherein R represents independently for each occurrence H; R″ representsH or alkyl; and n is
 2. 16. The method of claim 1, wherein R representsindependently for each occurrence H; the two instances of R′ takentogether represent —(CH₂)₄—; and R″ represents H or alkyl.
 17. Themethod of claim 1, wherein R represents independently for eachoccurrence H; the two instances of R′ taken together represent —(CH₂)₄—;R″ represents H or alkyl; and n is
 2. 18. The method of claim 1, whereinR represents independently for each occurrence H; the two instances ofR′ taken together represent —(CH₂)₄—; R″ represents H; and n is
 2. 19.The method of claim 1, wherein the compound is selected from the groupconsisting of:


20. The method of claim 1, wherein the mammal is a human.
 21. The methodof claim 20, further comprising the step of: co-administering to themammal in need thereof a therapeutically effective amount of a statinselected from the group consisting of atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,rosuvastatin, and simvastatin.
 22. The method of claim 18, wherein themammal is a human.
 23. The method of claim 22, further comprising thestep of: co-administering to the mammal in need thereof atherapeutically effective amount of a statin selected from the groupconsisting of atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.